The experiments proposed in project 3 will extend the neuroimaging studies of human subjects (Project 1, Dr. Breiter) and rodents (Project 2, Dr. Marota) to examine the cellular mechanisms underlying the interaction between pain and opioid addiction. Many studies have demonstrated that the central dopaminergic system is critical to rewarding, memory formation, and addiction to drugs of abuse. Similarly, the dopaminergic system has been shown to play a significant role in pain and pain modulation. Current data also suggest that brain regions such as nucleus accumbens (NAc) may receive converging inputs from both nociception and the opioid effects. In this project, as well as in project 2, a rat model of morphine conditioned place preference (mCPP) and of hindpaw monoarthritis will be used to mimic opioid addiction and chronic pain, respectively. We hypothesize that activation of dopamine receptors (DR) within mesolimbic brain regions such as NAc associated with mCPP and hindpaw monoarthritis would contribute to the interaction between mCPP and pain behaviors, which would be regulated by the glutamatergic and dopaminergic interaction within NAc via the cyclic AMP (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway and mitogen-activated protein kinases (MAPK). This main hypothesis will be examined using pharmacological tools, immunohistochemistry, Western blot, real-time RT-PCR, ELISA, and protein kinase activity assay to accomplish three specific aims: (1) To examine the behavioral interaction between mCPP and hindpaw monoarthritis;(2) To investigate the role of brain DR in the interaction between mCPP and pain behaviors;and (3) To explore the DR-mediated cellualr mechanisms of the interaction between mCPP and pain behaviors. Together with the data obtained from project 1 and project 2, we expect that this project will provide novel information regarding the interaction between pain and opioid addiction at the cellular and molecular level.